The overall goal of this proposal is to optimize a challenging skeletal rearrangement of the methanoquinolizidine akuammiline scaffold and to develop an advanced interrupted Fischer indolization reaction for the enantioselective synthesis of indoline- or indolenine-containing natural products. More than 30 akuammilines have been isolated and these alkaloids possess promising biological activities encompassing the following therapeutic areas: pain, depression, cancer, diabetes, inflammation, and herpes simplex virus (HSV). Along with their bioactivities, these compounds are structurally complex; only four akuammilines have been synthesized since the fist isolation in 1875. With the chemistry proposed, I will: learn about the skeletal reactivity of akuammilines that may give insight into molecular reactivity that may impact future synthetic designs, develop new methodologies, and access structurally diverse and biologically active akuammilines that have not been synthesized. The goals of this proposal will be accomplished through two specific aims. First, the exploration and optimization of the methanoquinolizidine rearrangement of some akuammilines will provide rapid access to related natural products comprised of pyrrolidinoindoline frameworks from related systems. This chemistry will yield the first total synthesis of akuammiline (-)-11-methoxyvincorine, an anti-cancer agent that reverses multi-drug resistance. Next, an interrupted Fischer indolization reaction will be developed such that the product of the complexity-generating reaction contains vicinal quaternary centers. This unprecedented reaction will allow for the synthesis of two additional akuammiline alkaloids that have not yet been accessed synthetically, namely (+)-akuammiline and biologically active (-)-?-akuammigine. Lastly, I would like to state that the compounds constructed throughout the work presented in this proposal will be submitted for biological evaluation.